Method of manufacturing a generator which produces radio-isotopes and has an improved elution efficiency,and generator obtained by this method

ABSTRACT

IT HAS BEEN FOUND THAT THE ELUTION EFFICIENCY OF GENERATORS WHICH PRODUCE RADIOACTIVE ISOTOPES AND CONTAIN AL2O3 AS THE ADSORBENT MAY BE GREATLY IMPROVED. THE IMPROVEMENT IS OBTAINED BY PROVIDING THE ADSORBENT OF THE GENERATOR WITH AN OXIDANT BEFORE FIRST USE OF THE GENERATOR. THE OXIDANT MUST HAVE A STRONG AFFINITY FOR THE SUBSTRATE. SUITABLE OXIDANTS ARE CHROMATES AND DICHROMATES.

- US. Cl. 252301.1 R

United States Patent 3,785,990 METHOD OF MANUFACTURING A GENERATOR WHICHPRODUCES RADIO-ISOTOPES AND HAS AN IMPROVED ELUTION EFFICIENCY, ANDGENERATOR OBTAINED BY TI-HS METHOD Harm Martinus Benjamins, KoosKortenoeven, and Helena Panek-Finda, all of van Houtenlaau, Weesp,Netherlands No Drawing. Filed Feb. 29, 1972, Ser. No. 230,502 Claimspriority, application Netherlands, Mar. 2, 1971, 7102716 Int. Cl. C09k3/00 4 Claims ABSTRACT OF THE DISCLOSURE It has been found that theelution etiiciency of generators which produce radioactive isotopes andcontain A1 0 as the adsorbent may be greatly improved. The improvementis obtained by providing the adsorbent of the generator with an oxidantbefore first use of the generator. The oxidant must have a strongaflinity for the substrate. Suitable oxidants are chromates anddichromates.

The invention relates to a method of manufacturing a generator whichproduces radioisotopes.

Radionuclides having a half-life of a few hours to a few days are usedin medicine for diagnostic purposes. To prevent the occurrence ofradiation damage in the tissues as far as possible, preferablyradionuclides are used which are pure gamma radiators. The optimum gammalines lie between 100 and 400 kev.

In addition to Sr and In especially Tc is being increasingly used. Thisradio-active technetium isotope may be used for the above indicatedpurpose as such but it is also suitable to label other substances such,for example, as albumins.

The radioisotope suitable for medical use is obtained inter alia from agenerator, which frequently is referred to as a cow or milker. Theradioisotope then is marketed in the form of the generator. The user maywithdrawn the desired radioisotope from the generator respectively. Suchinstantaneous production is of great practical importance because of therapid decay of a suitable radioisotope.

An isotope generator is obtainable by filling a container provided withan inlet and an outlet with an adsorbent material to which a radioactiveparent isotope is then applied. If desired, the generator may beprovided with seals which permit sterile use of the generator(Netherlands patent application No. 6,607,699, PHN. 1670). A frequentlyused adsorbent is A1 0 Generally an adsorbent largely consisting of A1 0is used in producing the aforementioned Tc generator.

The radioactive parent isotope present on the adsorbent by its decayproduces the daughter isotope, which is of interest for medical purpose,with the emission of radiation. In the Tc generator radioactivemolybdenum in the form of a molybdate is used as the parent isotope. TheTc produced from M0 by radioactive decay will mainly be in the form ofthe pertechnetate.

In the operation of the generator a washing liquid or eluent is admittedat the top through the inlet. The eluent traverse the adsorbent andcarries along the radioactive daughter isotope present. The eluenttogether with the radioactive daughter isotope dissolved in it leavesthe generator at the bottom and is collected in a receiver which ifdesired may be rigidly secured to the generator proper. The parentisotope is hardly, or not at all, displaced over the adsorbent by theeluent. A suitable eluent is an isotonic salt solution such, forexample, as a 0.9% common salt solution.

Several tests have been carried out with the aforedescribed isotopegenerator. From the various test it has been found that the efliciencyof a generator which con tains an adsorbent mainly consisting of A1 0greatly fluctuates and under certain conditions may be very low. Theterm efiiciency is used herein to mean the ratio between the amount ofradioactive daughter isotope actually obtained at elution and the amountof radioactive daughter isotope which could theoretically have beenobtained.

The fluctuations in the efliciency of the generator and the low level ofefliciency may be read from Table I of German Offenlegungsschrift(pre-published German patent application) No. 1,929,067 which gives dataabout the yield of a Tc generator. According to this Offenlegungsschriftthe efiiciency of an isotope generator may be increased if in the use ofthe generator a washing agent is used which contains an oxidant. Such awashing agent may simply be prepared by adding, for example,

sodiumhypochlorite to an isotonic solution and acidifying the mixture.

We have found that the use of the washing agent suggested in theaforementioned Olfenlegungsschrift has the following disadvantages:

(I) The stated increase in etficiency is not yet optimal at the firstelution(s) of the generator. This means that in the period during whichthe generator has its highest activity and is of greatest interest tothe user no maximal improvement in efficiency is achieved.

(2) The use of a washing liquid which contains an oxidant may result inan eluate containing this oxidant. This greatly reduces the usability ofthe eluate, for a liquid containing for example, chlorine cannot be usedas an injection preparation without further processing. The necessaryworking up of the eluate implies a reduction of radioactivity and theloss of the sterility of the eluate, which effects both aredisadvantageous.

(3) The presence of oxidants in the washing liquid (eluent) and eluateresults in that inlet and outlet reedles become seriously effected.

The proposed step of improving the efiiciency has to be taken by theuser of the generator himself.

We have now found a new method of manufacturing an isotope generatorwhich contains an adsorbent mainly consisting of A1 0 The generator madeby the method according to the invention has a high efiiciency and doesnot have the aforementioned disadvantages.

Before going into particulars of the new process according to theinvention it would appear to be desirable for a good understanding firstto expound the knowledge we have gained of the problems inherent in agenerator, on which knowledge the present invention is based.

From tests we have a correlation between the efficiency fluctuations andthe low efficiency level of a generator containing A1 0 as an adsorbentand on the other hand the amount of radiation produced by the generator.More particularly it has been found that the efficiency fluctuationsincrease and a tendency to very low values of the efficiency occurs ifthe radioactivity produced by a generator exceeds from about 100 mCi.The level of the radioactivity at which this phenomenon occurs dependsto a certain extent on the manner in which the generator has beenmanufactured and on the dimensions of the generator. For example, in aTo generator a reduction in efiiciency from 65-80% to about 25-50% isproduced when the radioactivity of the generator exceeds about 100-450mCi. Although hitherto it has not been possible to explain phenomenonfully, we have evolved the hypothesis that in that part of the generatorin which the radioactivity exceeds the above-mentioned values theradiation produces a chemical and physical change in the generatingsystem which comprises the absorbent, the parent isotope and thedaughter isotope, the whole in the aqueous environment of the eluent.These changes are such that transport of the radioactive daughterisotope through the adsorbent is no longer possible or at least ishighly retarded. The further investigation was directed to the findingof means of counteracting the degeneration of the generator system dueto strong radiation.

Surprisingly it has been found that the said degeneration may be greatlyreduced or even prevented if at least at the regions in the generator inwhich there is strong radiation the generator system it brought into anoxidizing condition.

More particularly the invention relates to a method of manufacturing anisotope generator in which a container provided with an inlet and anoutlet is filled with an adsorbent mainly consisting of A1 to which aradioactive parent isotope is applied, and the invention ischaracterized in that even before first use of the generator theadsorbent is brought to an oxidizing condition by the application of anoxidant.

The oxidant to be used according to the invention preferably should havea strong aflinity to the A1 0 adsorbent, for it is important that whenthe generator manufactured by the method according to the invention isused the washing agent used should not remove the oxidant from theadsorbent, but on the contrary it forms part of the substance of theinvention that the oxidant is fixed as securely as possible in theregion of the radiation field, i.e. of the parent isotope.

A person skilled in the art may readily select from the large assortmentof available oxidants a substance having the required aflinity for A1 0We have achieved very good results with the use of chromates anddichromates, particularly alkali metal chromates and dichromates.

The application of the oxidant may be effected by a known method.Preferably a solution of the oxidant is used. If desired, the solventmay be removed from the adsorbent, for example by drawing off at areduced pressure. When water or an aqueous salt solution is used as thesolvent it need not be removed from the adsorbent.

The amount of oxidant to be applied depends on various factors. Some ofthese factors are the radioactivity level and the shape of thegenerator, the position of the parent isotope on the adsorbent, theconcentration of the oxidant in the solution used and the nature of theoxidant.

By means of comparatively simple tests a person skilled in the art mayhimself determine the amount of oxidant which provides satisfactoryresults in a given situation. It should be borne in mind that for asatisfactory effect it is necessary for the substrate material to beprovided with the oxidant as effectively as possible in and about theregion in which the parent isotope is present.

Consequently, when the parent isotope is readily accessible, for examplewhen the parent isotope is present in the upper layer of the adsorbent,as is usual, it is sufficient to apply a small amount of a concentratedsolution of an oxidant.

When the parent isotope is not taken up in the upper layer of theadsorbent a larger amount of a solution of an oxidant is desirable.

Tests carried out with a Tc generator which had been manufactured by themethod according to the invention and in which an aqueous potassiumdichromate solution was used as the oxidant have shown that satisfactoryresults are obtained if at least 3 mg. of potassium dichromate dissolvedin a few milliliters of water is present.

Finally it should be noted that when sterile generators according to theinvention are manufactured the treatment with the oxidant may beeffected either before or after sterilization.

The invention will now be illustrated by the following example.

4 EXAMPLE Containers provided with an inlet and an outlet, which in theart are generally referred to as cartridges, were filled with an A1 0adsorbent and then processed in the following manner.

(1) Treatment with a molybdate solution containing radioactive M0.

The pH of the solution was 1 to 2.

(2) Washing with ml. of an isotonic salt solution. (3) If requiredsterilization at C. for 20 minutes.

The generators obtained by the above, known method were then treatedwith an aqueous salt solution in which potassium dichromate had beendisolved. The amount of potassium dichromate and the volume of the saltsolution were varied within wide limits, as will be seen from thefollowing Table I. As a reference, a generator without potassiumbichromate has been inserted into Table I.

TABLE I [Survey of some manners of pretreatment of generators]Sterilization before or after the Generator Treatment with dichromateaccording to dichromate number the invention treatment (1 (reference).

6 mg K2C1207 in 5 ml. of salt solution.. After.

Do. 12 mg. K201701111 5 ml. of salt solution-. Do. do Do. 12 mg. K2Cr2Oin 60 ml. of salt solution.-- Do. -rln Do. 6 mg. KzCrz0 in 5 ml. of saltsolution... Before.

n Do. 12 nag. K2OrzO1 in 5 ml. of salt solution- Do. n Do. 12 mg.K2Clz07 in 60 ml. of salt solution... Do. d0 Do. 6 mg. KzC12O7 in 5 ml.of salt solution. Do. -do Do. 6 mg. KzOr2O in 3 ml. of salt solution Do.16- ..rln Do. 17 6 mg. K2Cr2O7 in 1 ml. of salt solution D0. 18.-. doDo. 3 mg. K2CrzO in 5 m1. Do. 0 Do. Do. D0. of salt solution"--- Do. D0.of salt solution-. Do. Do. 1 mg. KzClzO1 in 3 ml. of salt solution...Do. 28.-- 1 mg. K2Cr2O in 3 ml. of salt solution. Do. 29..- 1 mg.K2CrzO7 in 1 ml. of salt solution Do. 30.... -do Do.

The operation of the generators obtained by the method according to theinvention was tested by eluting them in the usual manner and determiningthe yields of radioactive daughter isotope in the eluates obtained.

The efiiciencies obtained are listed in Table II.

TABLE II [Elution eflleiencies of a number of Te generators as afunction of the pretreatment (compare Table 1)] Generator Elution number(see Table 1) 1st 2d 3d 4th 7th 12th TABLE IIContinued Between each twosuccessive elutions there was a time interval of at least 22 hours.

Table II shows that the elution efficiency of the generators 25 to 30which contain a comparatively small amount of oxidant is appreciablylower than that of the generators 1-24 which contain larger amounts ofoxidant. The reference generator without oxidant gives a very pooryield.

The table shows that at the twelfth elution the difierences in elutionefliciency are substantially eliminated. This may readily be explainedby considering that at the twelfth elution the radioactivity of thegenerators, which initially was 300 mCi, had fallen to an extent suchthat the limit value below which the influence of the radiation on theetficiency is absent or at least greatly reduced is passed.

What is claimed is:

1. In the method of manufacturing an isotope generator in which acontainer provided with an inlet and outlet is filled with an adsorbentconsisting mainly of A1 0 to which adsorbent a radioactive parentisotope is applied, the improvement which comprises bringing theadsorbent to an oxidizing condition by applying to the adsorbent anoxidant which is strongly bound to the adsorbent prior to the firstelution.

2. The method of claim 1 wherein the oxidant is a chromate ordichromate.

3. The method as claimed in claim 2 characterized in that the A1 0adsorbent to which molybdenum containing Mo has been applied as a parentsubstance is treated with an aqueous which contains at least 3 mg. ofpotassium dichromate.

4. An isotope generator obtained by the method of claim 1.

References Cited UNITED STATES PATENTS 3,468,808 9/1969 Arino 252--301.13,561,932 2/1971 Gruverman et a1. 23-312 3,664,964 5/1972 Haney et a1.252-364 CARL D. QUARFORTH, Primary Examiner R. L. TATE, AssistantExaminer US. Cl. X.R.

23-252 R; 250106 T; 424l UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent No. 3,785,990 (PHN 5464) Dated January 15, 1974Inventofls) MARTINUS BENJAMINS ET AL It 15' certified that error appearsin the above-identified patent and that said Letters Patent are herebycorrected as ,shown below:

' Column 1, line 8, after "Netherlands" insert assignor to U.S,. PhilipsCorporation, New York,

Column 6, line l2, after."aqueous" insert "solution".

Signed and sealed this 16th day of July 1974.

(SEAL) Attest: I

GIBSON JR. c. MARSHALL DANN g t ng Officer Commissloner of PatentsUNITED STATES PATENT OFFICE 7 CERTIFICATE OF CORRECTION Patent No.3,785,990 (PHN 5464i Dated Januarv 15, 1974 Inventofls) MARTINUSBENJAMINS ET AL It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 1, line 8, after "Netherlands" insert assignor Column 6, line 12,after "aqueous" insert "solution".

Signed and sealed this 16th day of July 1971 (SEAL) Attest:

M. GIBSON JR. c. MARSHALL DANN g ting Officer Commissioner of Patents

